Abstract
Lymphocyte signaling cascades responsible for anti-tumor cytotoxicity and inflammatory cytokine production must be tightly regulated in order to control an immune response. Disruption of these cascades can cause immune suppression as seen in a tumor microenvironment, and loss of signaling integrity can lead to autoimmunity and other forms of host-tissue damage. Therefore, understanding the distinct signaling events that exclusively control specific effector functions of “killer” lymphocytes (T and NK cells) is critical for understanding disease progression and formulating successful immunotherapy. Elucidation of divergent signaling pathways involved in receptor-mediated activation has provided insights into the independent regulation of cytotoxicity and cytokine production in lymphocytes. Specifically, the Fyn signaling axis represents a branch point for killer cell effector functions and provides a model for how cytotoxicity and cytokine production are differentially regulated. While the Fyn–PI(3)K pathway controls multiple functions, including cytotoxicity, cell development, and cytokine production, the Fyn–ADAP pathway preferentially regulates cytokine production in NK and T cells. In this review, we discuss how the structure of Fyn controls its function in lymphocytes and the role this plays in mediating two facets of lymphocyte effector function, cytotoxicity and production of inflammatory cytokines. This offers a model for using mechanistic and structural approaches to understand clinically relevant lymphocyte signaling.
Highlights
Domain Structures of FynSrc-family of non-receptor tyrosine kinases are pleiotropic in nature and multiple family members, including Fyn, are ubiquitously expressed in multiple cell types
Lymphocyte signaling cascades responsible for anti-tumor cytotoxicity and inflammatory cytokine production must be tightly regulated in order to control an immune response
Fyn–adaptor protein (ADAP) binding occurs exclusively in lymphocytes, and activation of this pathway is mediated by an interaction between the Fyn SH2 domain and the pYDGI motif of ADAP corresponding to residues 625–628 [9]
Summary
Src-family of non-receptor tyrosine kinases are pleiotropic in nature and multiple family members, including Fyn, are ubiquitously expressed in multiple cell types This allows them to control a variety of cellular functions and highlights the need for maintaining signaling integrity both in terms of enzymatic activity and substrate specificity [13]. The SH2 and SH3 domains allow Fyn to position substrates adjacent to the bilobal tyrosine kinase (SH1) domain at its C-terminus (Figure 1A) [4] Both the N- and C-terminal lobes of the SH1 domain contain regulatory sequences (the C-Helix in the N-terminal lobe and the activation loop in the C-terminal lobe) that control ATP-binding and phosphate transfer [21,22,23]. The SH domains and quaternary structure of Fyn enable it to act in multiple facets of killer cell effector function by providing the substrate specificity and control of enzymatic activity required for regulation of divergent signaling
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